The broad, long-term objectives of this laboratory are to understand the immunological mechanisms[unreadable] underlying allergic lung disease. This proposal specifically will determine the earliest innate immune[unreadable] signaling pathway activated by allergens that conditions the lung for subsequent allergic lung disease.[unreadable] Further, we will determine the relationship between allergenic proteinases in home environments and the[unreadable] development of childhood asthma. Recent studies indicate that allergic asthma is the result of failure of[unreadable] immune tolerogenic mechanisms that are normally activated to suppress inflammatory responses to[unreadable] inhaled antigens. Commonly used experimental allergens such as ovalbumin are only transiently capable[unreadable] of avoiding tolerance and inducing robust airway inflammation and then only if administered initially[unreadable] remotely from the lung followed by airway antigen challenge. In contrast, we have developed more potent[unreadable] allergens derived from sources implicated in human allergic disease. Without requiring special adjuvants[unreadable] or protocols for administration, these fungal and pollen-derived allergens strongly induce allergic lung[unreadable] inflammation by bypassing airway immune tolerogenic mechanisms. These potent allergens contain strong[unreadable] proteinase activities that account entirely for their ability to induce and sustain chronically the asthma[unreadable] phenotype. Although non-fungal proteinases exist and are implicated in human asthma and other allergic[unreadable] disorders, our data indicate that dust from homes of asthmatic children contains primarily fungal[unreadable] proteinases.[unreadable] We therefore propose the novel hypothesis that proteinases represent an essential environmental adjuvant[unreadable] factor that is responsible for inducing allergic disease, especially in early life. The aims of this proposal are[unreadable] therefore to: 1. To evaluate the association between fungal proteinases and childhood asthma; and 2. To[unreadable] functionally characterize a novel innate signaling pathway of the airway activated by proteolytic allergen.[unreadable] We will conduct a case-control study involving Houston-area children with and without asthma to[unreadable] understand the association between active proteinase in house dust and asthma and, further, prepare[unreadable] allergens from fungi isolated from homes of asthmatic children and determine the innate immune[unreadable] mechanism by which they elicit disease in mice. This proposal links human and animal studies to unravel[unreadable] the fundamental immune mechanisms underlying allergic inflammation with the intent to develop novel[unreadable] therapies for asthma.